Download Chronodisruption, cell cycle checkpoints and DNA repair

Indian Journal of Experimental Biology
Vol.52, May 2014, pp. 399-403
Overview
Chronodisruption, cell cycle checkpoints and DNA repair
Rachel Ben-Shlomo
Department of Biology, Faculty of Natural Sciences
University of Haifa – Oranim, Tivon 36006, Israel
Chronodisruption, a disturbance in "natural" daily light/dark regulation, is possibly linked to disturbances in cell cycle
homeostasis. The association and the synchronization between circadian rhythms and mitosis are not yet clear. The circadian
oscillator is involved in the major cellular pathways of cell division. A molecular link between the circadian clock and the
mammalian DNA damage checkpoints has been outlined. Analyses suggest an association between light disruption and
obstruction of the cell cycle homeostasis. Disruption in the homeostatic control of the cell cycle has been associated with
cancer and acceleration of malignant growth, possibly as a result of the interruption of DNA damage check-points. Studies
further indicate that light signal during the dark phase affects the transcription level of a substantial number of genes that are
associated with cell cycle progression, cell proliferation and tumorigenesis. Indeed, the International Agency for Research in
Cancer categorized "shift work that involves circadian disruption" as possibly carcinogenic. In this review the current
finding on light pollution and its potential influence on cell cycle check-points and DNA repair is presented.
Keywords: Cell cycle homeostasis, Chronodisruption, Circadian oscillator, DNA damage
Living eukaryote cells present numerous periodic
processes that oscillate in various paces. Two of the
better characterized cell autonomous oscillators are
circadian clock and cell division cycle. Each of these
oscillatory systems seems to be self-directed and
regulated by its own pacemaker. The period length of
the circadian rhythm is about a day (~24 h) and the
clock is compensated for various environmental
fluctuations such as temperature. The period length of
cell cycle is wide-ranging from minutes to days and
the cycle is highly influenced by environmental
variables like nutrient availability or temperature1,2.
Although there appears to be no link between these
two oscillators, none the less, the circadian clock
oscillators and the cell cycle oscillators are combined
in several ways. The aim of this review is to provide
an entrée into an exciting and promising new theme of
chronobiology that links regulation of circadian
oscillator to that of cell cycle homeostasis.
The circadian nature of cell division
A fundamental characteristic of circadian clocks in
eukaryotes is that they are based on cell-autonomous
interacting transcriptional/translational feedback loops
that drive cyclical gene expression, which ultimately
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underlies many of the rhythms manifested by
organisms3. A number of the cell cycle oscillator core
genes also show a circadian expression4. Modification in
expression levels of various canonical circadian clock
genes results in changes in the level of several cell cycle
genes, as well as in numerous cell cycle disorders5.
Although period length of cell cycle is variable, a
large variety of eukaryotic organisms exhibits a
circadian mode of cell division6. Hence, the nature of
the association between the two oscillators, whether
correlative or causative, is not yet clear. A support for
a causal association between the circadian and the cell
cycle oscillators is derived from several findings,
suggesting that the daily oscillator is involved in
gating the entry and exit for cell division7,8.
The gating attribute of the circadian clock may be
conserved from unicellular organisms to vertebrates.
In cyanobacteria, Yang et al.9 showed a slowdown in
the progress of cell cycle in a specific phase of the
circadian interval. In yeast, DNA synthesis (S-phase)
is timed to set apart of the oxidative phase, and in
zebrafish, arrays of various cells are synchronized by
the circadian oscillator to go into S-phase towards the
end of the light phase11. Along these lines, a daily
mitotic cycle may be an evolutionary advantage,
enabling cells to synchronize DNA synthesis to a
specific time (dark phase for instance), whereby cells
are able to escape deleterious and/or mutable effects
such as UV radiation or oxidation.
400
INDIAN J EXP BIOL, MAY 2014
Gating the cell cycle by the circadian oscillator can
be accomplished by a molecular crosstalk between the
core oscillator genes involved in the two rhythmic
processes5. The gene period (per) is one of the bona
fide circadian clock canonical genes. The mammalian
period paralogues Per1 and Per2 are molecularly
linked to repression of G1-S transition, while the
circadian transcription factors Bmal1 and Clock are
associated with G2-M transition5,12-14. Additional
putative role for BMAL1 protein is in suppressing
cells from undergoing S-phase while reactive oxygen
Species (ROS) levels are high15.
Further support for a molecular crosstalk mode
of gating operation was found recently by
Kowalska et al.16, who showed that the protein
NONO, a multifunctional nuclear protein, operate
together with the circadian protein PER, in controlling
the circadian expression of the cell cycle checkpoint
gene p16-Ink4A. The circadian control of p16-Ink4A
via NONO is necessary for gating exit from cell cycle
G1 phase16,17.
Cell cycle checkpoints and DNA damage control
In contrast to the continue cycling of the circadian
pacemaker, the cell cycle oscillator is characterized
by discrete checkpoints that monitor the integrity of
DNA replication and repair7,18. At least four major
checkpoint pathways (S-phase, DNA damage,
topoisomerase II – dependent and spindle assembly
checkpoint) regulate phase transition during the cell
cycle process19.
The circadian oscillator is implicated in the
checkpoint cellular pathways of the cell cycle20-22. An
involvement and the probable causative association
between the core circadian oscillator genes and the
cell cycle checkpoint processes are further
manifested. A molecular association between the
mammalian DNA damage checkpoints and the
circadian clock genes has been proposed20,21,23,24.
Modifications in expression levels of various
circadian clock proteins alter checkpoint responses24.
PER1 protein is molecularly involved with DNA
damage checkpoint protein ataxia telangiectasia
mutated (ATM) and with checkpoint kinase 2
(Chk 2). Overexpression of PER1 induces apoptosis,
while its inhibition reduces apoptosis23. Mutation in
Per 2 gene eliminates cell response to gamma
radiation and deregulates expression of several cell
cycle checkpoint genes such as cyclin D1, cyclin A,
mdm-2, gadd45 and c-myc25.
Another implicating putative circadian clock gene
is timeless (tim). The gene is a key element of the
circadian oscillator in the fruit fly Drosophila
melanogaster. In mammals, the probable descendant
homologue TIM protein is not a true orthologue of
Drosophila TIM, and its functional association with
the circadian oscillator is under debate. A recent study
suggested a probable role for TIM in the mammalian
circadian clock speed and resetting26. The mammalian
TIM protein is involved in the cell cycle oscillator and
is coordinated the intra-S checkpoint response to
DNA damage induced by UV radiation21.
Considering the circadian mode of cell
proliferation and the causal association with the DNA
damage checkpoint, an important question is whether
altering circadian cycle can also affect the dynamics
of cell division, with further comprehensible
implications for tumor growth27-30. Recent studies
point out that interference in gene expression of the
circadian oscillator can lead to cell cycle disorders
and/or unrestrained cell proliferation5. Indeed, in
mammals, the association between malignancy and
the interruption of the circadian cycle and interference
in the regulation of cell cycle has been recognized for
several years31,32. However, most surveys are
epidemiological studies, and there are no definitive
investigations with a direct link between light-atnight, chronodisruption and cancer rate33.
Light at night, chronodisruption and malignancy
Light is the most prominent environmental signal
that regulates daily and seasonal timing and as such,
is an influential regulator of physiology and
behaviour. An important adaptive feature of circadian
clocks is that they can be synchronized (entrained) to
local time. Synchronization of circadian oscillators is
attained because light has acute effects on the levels
of the clock’s components3.
Modern life every so often comes across
disturbances in "natural" light/dark cycles. Light
phase is prolonged by light-at-night (LAT) and
various professions involve night work or shift work.
In addition, lights turned on during the dark phase
generate light pulses, further triggering interferences.
The
resulting
chronodisruption
can
cause
complications for circadian clock organization.
A substantial inference is whether such altering of
circadian organization and entrainment also affects
the dynamics of cell division. If so, the disruption of
the circadian oscillator per se can further influence
cancer growth and tumor progression28,34,35.
BEN-SHLOMO: CHRONODISRUPTION, CELL CYCLE CHECKPOINTS AND DNA REPAIR
There is increased evidence relating LAN to
various malignancies in general and to breast cancer
in particular. Nighttime satellite images and electricity
consumption were monitored to estimate the
correlation between LAN and various cancer
incidents. The results indicate a significant association
between rates of breast cancer and LAN36,37.
Wu et al.38 showed that to some extent, exposing
transgenic rats to LAN accelerated tumor growth
in vivo, through continuous activation of IGF1R/PDK1 signaling. Nonetheless, the causative
pathway of this association is not yet clear.
Night-shift work has long been associated with
ill-health and the risk of cancer33,39-41. Consequently,
the International Agency for Research in Cancer
(IARC) classified "shift work that involves circadian
disruption" as possibly carcinogenic40. In the past
few years, there have been numerous supportive
meta-analyses and evidence showing that night work
does play a role in breast cancer42,43. However, there
are no clear indications for the exact pathway linking
shift-work, chronodisruption and malignancy.
Nocturnal light pulses entrain and synchronize the
circadian clock and are long known to affect
physiology and behaviour. In mammals, evidence
suggests that light pulses also operate as stressors that
affect thermoregulation and impose a key threat to
the physiological homeostasis of the organism44.
Ben-Shlomo and Kyriacou29 showed that light signal
during the dark phase consistently activates
transcription of numerous stress genes which are
involved in the regulation of cell cycle progression, as
well as levels of genes that are associated with the
various cell cycle checkpoints. Thus, light pulse can
operate as an environmental indicator and/or stressor
that promptly affect transcription levels of genes that
directly control cell cycle progression and play an
indispensable role in cancer proliferation and survival.
Circadian disruption has been associated with
interference to the homeostatic control of cell
division, associated with malignancy, possibly as a
result of interruption in the cell cycle DNA damage
checkpoints31,32,45-47. Chronodisruption by dim light at
night or chronic jet lag accelerates tumor growth48.
Wood et al.49 suggested that the circadian clock gates
tumor cell proliferation by coordinating clockcontrolled proteins.
Ben-Shlomo and Kyriacou29,30 also showed that
light pulse during the dark phase affected a
considerable assembly of transcripts promoting cell
401
proliferation, including tumor suppressors, oncogenes
and genes that are involved in tumor growth and
metastasis. The results suggest an association between
light pulse, obstruction of the cell oscillator cycling
and tumorigenesis30. The molecular intracellular
signaling pathway(s) by which light regulates and
modifies the expression of genes related to cell cycle
and tumorigenesis is not yet known22. The increased
risk for malignancy among shift-workers raised the
debate of whether this is a causative phenomenon or a
multifaceted association45. Our results support the
alternative of a causative link between light signal
during the dark phase and the disruption of the cell
cycle homeostasis29,30.
The rapidity of tumor growth may also be related
to the circadian oscillator and thus, to be affected by
entrainment of the host clock. Consequently,
chronodisruption
may
speed
up
abnormal
proliferation27. Hence, the circadian oscillator also
drives daily cycles of detoxification drug metabolism,
i.e. toxicity and anti-cancer xenobiotic efficacy is
modified with the circadian time50. Consequently, a
corresponding approach can consider chronotherapy,
by means of using the circadian oscillator to
down-regulate cell proliferation and malignant growth
factors51.
Concluding remarks
The accumulated data presented here suggests that
artificial illumination via LAN, shift-work, and
chronodisruption affects regulation and expression of
genes that are associated with cell cycle homeostasis.
Most of the available data to date merely reveals an
association between the regulation of the circadian
rhythms and the cell cycle progression. Nonetheless,
the repeated found association and the suggested
causality clearly has implications for the topic of
whether there is an increased relative risk for cancer.
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